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Tuesday, May 15
12:00 pm Registration
1:30 Conference Introduction
1:35 Science and Serendipity: Discovery of Novel Adenosine A2A
Antagonists for the Treatment of Parkinson’s Disease
Allan Jordan, Ph.D., Team Leader, Medicinal Chemistry, Vernalis
plc
The human adenosine A2A receptor
regulates smooth and well-coordinated movement, in part by
modulating the activity of dopamine sensitive neurons in the
striatum. There is mounting evidence that adenosine A2A
receptor antagonists may provide a point of intervention for
Parkinson’s disease with a lower incidence of side effects. We
discovered that the (-)-diastereoisomer of the antimalarial drug
mefloquine is a reasonably potent and moderately selective adenosine
A2A receptor antagonist. This led to the identification
of several novel series of A2A antagonists, displaying
potency, selectivity and oral activity, alongside oral
bio-availability, excellent brain penetration and rapid onset of
action. This work cumulated in the discovery of BIIB014/V-2006,
which is now undergoing clinical trials. Studies leading toward the
discovery of these compounds and early clinical and pre-clinical
data for BIIB014/V-2006 will be described.
2:05 Dual NK3/NK1 Receptor Antagonism: A Novel Approach for
the Treatment of Psychotic Disorders
Patrick Schnider, Ph.D., Scientific Specialist, Medicinal
Chemistry, F. Hoffmann-La Roche
Schizophrenia is a chronic and debilitating
mental disease, which affects about 1% of the population. It
manifests as symptoms that fall into three categories: positive,
negative, and cognitive symptoms but mood is also often affected.
Current antipsychotic drugs bind to a variety of receptors but most
importantly to a sub-set of dopamine and serotonin receptors.
Although these treatments reduce the severity of positive symptoms,
there is a high need for improved medications due to their limited
effectiveness on negative and cognitive symptoms as well as severe
side effects including extrapyramidal symptoms, weight gain and
metabolic changes. Over the last decade, increasing evidence has
emerged that neurokinin (NK) receptors may effectively modulate
behaviors mediated by dopamine and serotonin. Several neurokinin
receptor antagonists have been tested in phase II clinical trials,
with no major side effects reported so far. The selective NK3
antagonist osanetant (Sanofi) showed efficacy on positive symptoms
in patients with schizophrenia, while the selective NK1 antagonist
aprepitant (MSD) displayed antidepressant and anxiolytic activity.
These results suggest that dual NK3/NK1 antagonism might be an
effective approach for the treatment of both positive and
negative/mood-like symptoms in schizophrenia patients. Here we
report on the discovery and characterization of potent new dual
NK3/NK1 antagonists.
2:35 The Melatonin Receptor Subfamily and Mental Disorders
Ralf Jockers, Ph.D., Research Director INSERM, Department of Cell
Biology, Institut Cochin
Depressive disorders have a lifetime prevalence
of 10-25% with increasing incidence in older people. Recent genetic
and pharmacological evidences suggest that members of the melatonin
receptor family may be involved in mental disorders. This G
protein-coupled receptor subfamily is composed of MT1 and MT2
receptors that respond to the circadian neurohormone melatonin and
GPR50, an orphan seven-transmembrane protein. A deletion variant of
the GPR50 gene has been associated with an increased risk of BDAD
and MDD. In an effort to discover the function of the orphan GPR50
we studied the heterodimerization of GPR50 with MT1 and MT2 and
identified profound functional modifications.
3:05 Networking Refreshment Break, Poster and Exhibit Viewing
3:45 GPCR Drug Development Using Peptide
Mimetics
Peter Cassidy, Ph.D., Chief Scientific Officer, Mimetica Pty Ltd.
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4:00 Technology Watch
New GPCR Modeling Toolkit with a Focus on Structural Refinement of
Homology Models
Christopher Higgs, Ph.D., MRSC, Senior Applications Scientist,
Schrodinger
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4:15 Computational Discovery of Eight Novel Peptide Agonists for G-Protein Coupled Receptors
Ronen Shemesh, Manager of Experimental Research, R&D,
Compugen Ldt.
G-protein-coupled receptors (GPCRs) represent the most important group of targets for therapeutics. The completion of the human genome revealed a large number of new GPCRs; however the identification of their natural ligands, and especially peptides, suffers from a low discovery rate, thus impeding development of therapeutics based on these potential drug targets.Compugen has developed a computational tool aimed at the discovery of unidentified GPCR peptide ligands encrypted in the human proteome. Hundreds of potential GPCR ligand peptides were predicted by machine learning related methods. In vitro screening of 33 of these peptides on a large number of GPCRs (152), including a group of orphan receptors, was conducted utilizing a universal Ca++ flux and cAMP assays. The screening revealed eight novel peptide agonists that specifically and dose dependently activated six different receptors. Some of the new ligands showed a distinct activation pattern to annotated GPCRs while others activated previously designated orphan GPCRs. In summary, the screening identified eight novel GPCR agonists. This discovery confirmed a computational method for the prediction of novel GPCR peptide ligands, that resulted in a repertoire of potential new GPCR activators.
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4:45 Technology Watch
GPCR Modeling with Discovery Studio and Pipeline Pilot
Jeffrey L. Nauss, Ph.D., Lead Training Scientific, Accelrys, Inc.
A brief overview will be presented of tools and capabilities in Discovery Studio and Pipeline Pilot that can be used for GPCR modeling. The focus will be on construction of the initial protein model followed by considerations for further refinement including the use of implicit membrane models. New functionality in the next releases will also be briefly mentioned.
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5:00 End of Day One
Wednesday, May 16
7:30 am Interactive Roundtable Discussions
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Topic: Hit ID and Lead Optimization for GPCRs – How to Get
Smarter?
Moderator: Allan Jordan, Ph.D., Team Leader, Medicinal Chemistry,
Vernalis
- How can we improve reliability and implementation of homology
models?
- How can we apply technologies such as fragments for GPCRs?
- What best practices for Hit Identification are employed?
- How can we best apply structure-based drug design to GPCRs?
Topic: Therapeutic Potential for Recently Discovered GPCR Peptide
Activators
Ronen Shemesh, Manager of Experimental
Research, R&D, Compugen Ldt.
- Drugability of peptides: What are the main features for such
candi dates?
- Peptides as scaffold: The potential of peptide activators to
leverage development of small molecule activators for GPCRs
- Peptides as research tools: How can peptides be utilized as a
research tool to help discovery of potential GPCR small molecule
antagonists
- Peptide activators and GPCR hetero-dimerization: How can
peptide discovery help in research and discovery related to GPCR –
GPCR interaction and reciprocal function.
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8:55 Chairperson's Remarks
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9:00 Deorphanization of GPCRs
Olivier Civelli, Ph.D., Professor and Chair, Neuropharmacology,
University of California Irvine
The superfamily of the GPCRs can be classified
into the somatosensory GPCRs (500-700 members) and
"transmitter" (about 360 members) GPCRs. Of the 360
transmitter GPCRs, 260 bind known ligands, while the others bind
ligands that have not been thus far described. These are the orphan
GPCRs, which carry the promise to lead us to the discovery of novel
physiological responses. We have devised a strategy to identify the
natural ligands of orphan GPCRs. This strategy ultimately led to the
discovery of 10 neuropeptide families. Interestingly, several of the
novel neuropeptides discovered as ligands of orphan GPCRs exhibit
regulatory roles on food intake, in particular two ligands of orphan
GPCRs, the neuropeptides orexins and melanin-concentrating hormone (MCH).
To understand the functional significance of the MCH system, we have
isolated a synthetic MCH receptor antagonist. This antagonist was
identified through the screening of synthetic combinatorial
libraries. When administered i.c.v., this antagonist has only a weak
and transient inhibitory effect on food intake. On the other hand,
when administered peripherally, it reduces nocturnal food intake and
induces significant metabolic changes. Using this selective
antagonist we thus can differentiate the central and peripheral
effects of the MCH system.
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9:45 Discovery of a Novel CB1R Inverse Agonist MK-0364 for the Treatment of
Obesity
Tung M. Fong, Ph.D., Director, Obesity & Metabolic Disorders, Merck Research
Laboratories
Diverse neuropeptide and neurotransmitter systems contribute to the regulation of energy balance. The development of highly selective ligands is anticipated to be applicable for the treatment of obesity and related disorders. Recent efforts aimed at discovering selective and potent CB1 receptor inverse agonist and other agents will be
highlighted.
10:15 Networking Coffee Break, Poster and Exhibit Viewing
10:45 Effects of Rimonabant on Pancreas and Adipose Tissue
Functions
Anne-Marie Galzin, Ph.D., International Deputy Head, Metabolism, Discovery Research, sanofi-aventis R&D
Rimonabant is the first CB1 receptor antagonist approved for the treatment of obese and overweight patients with associated risk factors, such as type 2 diabetes or dyslipidaemia. Recent data indicate that rimonabant has beneficial effects on glycaemia control and reduction of body weight, as well as on other cardiovascular risk factors, in patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas (RIO-Diabetes study) or treatment naive (SERENADE study). Moreover the favorable evolution of metabolic parameters is only partially (50%) weight loss dependent, suggesting a direct peripheral effect of rimonabant on glycemic control beyond that from weight loss alone. These results are found in various animal models of obesity and diabetes, which are suitable to explore the peripheral function of CB1 receptors. Special attention has been recently given to the adipose tissue and pancreas, where CB1 receptors are expressed at significant levels in both rodent and human tissues. Data will be presented supporting the hypothesis that rimonabant can control the differentiation process of the adipocyte, favoring its endocrine function, but not its energy storage properties. Moreover, rimonabant has also been shown to delay the development of hyperinsulinemia and pancreatic b-cell dysfunction in pre-diabetic and diabetic rodent models. These data are all consistent with direct peripheral contributions in the mechanism of action of rimonabant.
11:15 Discovery of Melanin-Concentrating Hormone R1 Antagonist
for the Treatment of Obesity: Taming hERG
Jing Su, Ph.D., Principal Scientist, Chemical Research,
Schering-Plough Research Institute
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activity of bicyclc[4.1.0]heptane 1, Structure-activity relationship
study on 1 was accomplished by utilizing solution phase parallel
synthesis. Several focused libraries were designed and synthesized
to quickly develop SAR. Further optimization led to the discovery of
compounds with excellent ex vivo activity and much reduced hERG
liability.
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11:45 Agonists of GPR119/GDIR Mediate Glycemic Control via Glucose Dependent Insulin and Incretin
Release
Rob Jones, Ph.D., Director, Medicinal Chemistry, Arena
Pharmaceuticals
Pancreatic b-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the GLP-1 receptor have shown significant promise as anti-diabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic b-cell mass. These effects are mediated via stimulation of cyclic AMP through b-cell GLP-1 receptors. We report that the Gas-coupled receptor GPR119 is largely restricted to insulin-producing b-cells of pancreatic islets. Based on the functional properties of GPR119 described herein, we propose terming this receptor GDIR (“glucose-dependent insulinotropic receptor”). Unlike receptors for GLP-1 and other peptides that mediate enhanced glucose-dependent insulin release, GPR119 has proven amenable to the development of potent, orally active, small-molecule agonists. The GPR119-specific agonist AR231453 significantly increased cyclic AMP accumulation and insulin release in both HIT-T15 cells and rodent islets. In both cases, loss of GPR119 rendered AR231453 inactive. AR231453 also enhanced glucose-dependent insulin release in vivo and improved oral glucose tolerance in wild-type mice, but not in GPR119-deficient mice. Diabetic KK/Ay mice were also highly responsive to AR231453. Orally active GPR119 agonists may offer significant promise as novel anti-diabetics acting in a glucose-dependent fashion.
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12:15 pm Luncheon Technology Workshop
Novel Cell-Based Technologies to Accelerate High-Throughput Screening at GPCRs
Richard Eglen, Ph.D., Vice President & General Manager, Life & Analytical Sciences, PerkinElmer,Inc. |
Sponsored by
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1:15 Session Break
1:40 Chairperson’s Remarks1:45 Utilizing Ligand Induced Conformational Change to Screen for Compounds Targeting G-Protein Coupled
Receptors
Brian F. O’Dowd, Ph.D., Professor, Departments of Pharmacology, University of
Toronto
2:15 Elucidating GPCR Allosteric Modulators
Annette Gilchrist, Ph.D., Founder, Caden BioSciences, Madison,
WI
G-protein coupled receptors (GPCRs) comprise the largest superfamily of receptors. They are the target for approximately half the world’s medicines. Most therapeutics targeting GPCRs activate (agonists) or inhibit (antagonists, inverse agonists) receptor signaling by binding the orthosteric site (site bound by endogenous agonist). In contrast, allosteric ligands modulate receptor function by binding to a site other than the orthosteric site on the receptor. Allosteric binding sites on GPCRs are attractive targets for the development of more selective and safer drugs. Presented will be the current state of allosteric modulator development for GPCRs with emphasis on the CNS and endocrinology receptors. Methods to identify and validate allosteric modulators of endogenous and synthesized modulators, their receptor interaction and the therapeutic prospects of allosteric ligands compared to orthosteric ligands will be discussed.
2:45 Assay Development and Results for Difficult GPCR
Targets
Tina Sepp, Ph.D., Multispan, Inc.
3:15 Networking Refreshment Break, Poster and Exhibit
Viewing
3:45 Close of G-Protein Coupled Receptor Conference
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